Durable responses with daratumumab seen after multiple prior regimens

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Targeting the CD38 antigen in myeloma by treatment with daratumumab led to deep and durable responses in patients who had received three or more prior regimens.

Note that the most frequently reported treatment-emergent adverse events were fatigue, anemia, nausea, and thrombocytopenia.

VIENNA -- Targeting the CD38 antigen in myeloma led to deep and durable responses in patients who had received three or more prior regimens, according to a study reported here.

Overall, 29% of 106 patients had objective responses with daratumumab, including stringent complete responses in 3% and very good partial response in 12%. Responses usually occurred within a month of starting treatment, and median duration of response was estimated a 7.4 months, though the upper limit of confidence intervals had yet to be reached.

Serious treatment-emergent adverse events occurred in 30% of the patients, including grade 3/4 severity in a fourth of patients, but no patient discontinued treatment because of adverse events, Sagar Lonial, MD, of Winship Cancer Institute and Emory University in Atlanta, reported at the European Hematology Association meeting.

"Daratumumab had remarkable single-agent activity in heavily pretreated and refractory myeloma patients who had exhausted other therapeutic options," Lonial said. "The efficacy was consistent across all subgroups. Responses were rapid, durable, and deepened over time."

"Daratumumab represents a new standard of care in this setting," he added.

A phase I/II trial of daratumumab (then known as GEN501) showed single-agent activity in patients with relapsed and refractory myeloma, including a 35% response rate in a subgroup of patients treated with one of the higher doses evaluated. The phase II trial reported by Lonial also showed superior efficacy of 16 versus 8 mg/kg of daratumumab, and evaluation continued with the higher dose.

Investigators in the multicenter trial enrolled patients who had received at least three prior lines of therapy or whose disease had proven refractory to both a proteasome inhibitor and an immunomodulatory drug, or imid (double refractory). The primary objective was overall response rate, and secondary objectives included progression-free survival (PFS), overall survival (OS), duration of response, and clinical benefit rate (objective response plus minimal response).

At data cutoff, 16 patients remained on treatment. The primary reason for discontinuation was disease progression (77% of discontinuations). Five patients discontinued because of adverse events unrelated to treatment with daratumumab (general health deterioration in two cases, H1N1 influenza, hypercalcemia, and spinal cord compression).

The patients treated at the 16 mg/kg dose had a median age of 63.5, and 12% of the patients were 75 or older. Three-fourths of the patients had International Staging System stage II or III (38% each) disease. The cohort's had a median disease duration of 4.8 years, and treatment history included a median of five prior regimens. All of the patients had received one or more immunomodulatory agent and one or more proteasome inhibitor. Additionally, 85 (80%) patients had undergone stem-cell transplantation.

All but three patients had proven refractory to the most recent therapy. More than 90% of the patients had disease that demonstrated refractoriness to three agents, 31% to four agents, and 11% to five agents. Additionally, two-thirds of the patients were refractory to three of four widely used agents: bortezomib (Velcade), lenalidomide (Revlimid), carfilzomib (Kyprolis), and pomalidomide (Pomalyst).

"This was an extremely difficult, treatment-refractory group of patients," Lonial said.

The treatment led to measurable reductions in myeloma-related paraprotein in a majority of patients, including reductions greater than 50% in 40 patients and greater than 90% in 17 patients. In addition to the objective responses, minimal responses occurred in 5% of patients, resulting in a clinical benefit rate of 34%. Prolonged therapy led to deepening of the initial response in multiple cases, Lonial said.

Objective responses were observed across all subgroups analyzed, including age ≥75, high-risk cytogenetics, extramedullary disease, number of prior lines of therapy, refractoriness to both imids and protease inhibitors, and refractoriness to specific prior therapies and combinations.

After a median follow-up of 9.3 months, 29 of 31 responding patients remained alive, and the 1-year survival was 65%. The median PFS was 3.7 months. Median OS has yet to be determined.

Infusion-related reactions occurred in 43% of patients. The reactions were grade 1 or 2 severity in all but 5% of cases, and no patient had a grade 4 reaction. The reaction occurred during the first infusion only in 90% of cases, Lonial said. No patient discontinued because of an infusion-related reaction.

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